Single-cell profiling reveals monocyte mitochondrial dysfunction in patients with cirrhosis progressing to acute-on-chronic liver failure

Abstract

ABSTRACT Background & Aims Patients with acute decompensation (AD) of cirrhosis are at a high risk of developing acute-on-chronic liver failure (ACLF), a syndrome characterized by multi-organ failure and high short-term mortality. Prospective studies addressing the cellular mechanisms that drive the transition from AD to ACLF are lacking. In this study, we aimed to determine whether peripheral immune cell subsets at hospital admission predict the progression from AD to ACLF and to delineate underlying molecular mechanisms. Approach & Results We prospectively enrolled 63 patients with AD and 15 healthy donors across five European centers, with a 90-day follow-up. Single-cell RNA sequencing was performed on peripheral blood mononuclear cells (PBMCs) from 16 patients with distinct trajectories and 4 controls. Progression to ACLF was associated with expansion of classical monocytes, particularly subcluster “C2”, which specifically displayed impaired energy metabolism with reduced oxidative phosphorylation. Genes encoding respiratory chain Complex IV were markedly downregulated. A C2-derived gene signature was enriched in two large international whole-blood cohorts (PREDICT, n=689; ACLARA, n=521), particularly in patients with bacterial infections, those developing ACLF, and non-survivors. Functional validation by respirometry in an independent AD cohort confirmed declining monocyte Complex IV–dependent oxygen consumption in patients with pre-ACLF. Conclusions We identified and validated a distinct monocyte subpopulation with defective energy metabolism in patients with AD with poor outcomes, suggesting a mechanistic link to ACLF development.

The authors' abstract, as published at the source. JHEP Reports, 2026 · DOI ↗